The Pharmacology of Sleep

1 Evolution of Concepts of Mechanisms of Sleep.- A. Introduction.- B. Brief Historical Overview.- C. Early Neurophysiological Concepts of Sleep (From Passive to Active).- D. Neurohumoral Concepts of Sleep Regulation.- I. Progressive Development of an Old Idea.- II. Sleep Factor Regulation Viewed Physiologically.- E. Neurochemical — Neurophysiological Concepts of Sleep Regulation.- I. Classical Neurotransmitters.- II. Neurotransmitters and Single-Unit Studies.- F. Final Considerations.- G. Summary.- References.- 2 Principles of Sleep Regulation: Implications for the Effect of Hypnotics on Sleep.- A. Basic Processes.- B. Sleep Homeostasis.- I. EEG Slow Waves as Indicators of “Sleep Pressure”.- 1. Global Changes During Baseline Sleep Episodes.- 2. Effect of Sleep Deprivation.- II. Ultradian Dynamics of Slow-Wave Activity and Spindle Activity.- 1. Baseline Sleep and Recovery Sleep After Sleep Deprivation.- 2. Neurophysiological Basis of Slow Waves and Sleep Spindles.- III. Homeostasis of REM Sleep and Interactions with Non-REM Sleep.- C. Effect of Hypnotics on Sleep and the Sleep EEG.- I. Benzodiazepine Hypnotics Alter the Sleep EEG.- II. Benzodiazepine-Receptor Agonists Have Similar Effects on the Sleep EEG.- III. Do Hypnotics Disrupt Sleep Homeostasis?.- IV. Effect of Benzodiazepine Hypnotics on Circadian Rhythms.- D. Concluding Remarks: Pitfalls in Pharmacological Sleep Studies.- E. Summary.- References.- 3 Principles of Chronopharmacology and the Sleep-Wake Rhythm.- A. Introduction.- B. Properties of Biological Rhythms.- C. Biological Rhythms as Adaptive Phenomena to Predictable Changes in Environmental Factors.- D. Temporal Distribution and Dosing Time of Therapies.- E. Concepts in Chronopharmacology.- I. Chronopharmacokinetics (or Chronokinetics) of a Drug.- II. Biomechanisms Presumably Involved in Chronokinetic Changes.- III. Chronesthesy of a Biosystem.- IV. Chronergy of a Chemical Agent.- V. Chronotherapy.- F. Drug Effects on Sleep, Anesthesia and Related Processes.- I. Anesthetics.- II. Ethanol.- III. Drug-Induced Drowsiness.- G. Shift Workers, Jet Lag and Sleeping Pills.- I. Shift Workers and Sleeping Pills.- II. Jet Lag, Sleeping Pills, Melatonin and Bright Light.- H. Summary.- References.- 4 Pharmacology of the Catecholaminergic System.- A. Introduction.- B. Amine-Depleting and Synthesis-Inhibiting Substances.- I. Catecholaminergic-Depleting Substances: Reserpine.- II. Dopamine-ß-hydroxylase Inhibitors.- III. Tyrosine Hydroxylase Inhibitor.- IV. Norepinephrine Uptake Blockers.- V. In Conclusion.- C. Adrenergic Agonists and Antagonists.- I. ?1-Antagonists (Phenoxybenzamine, Prazosin).- II. ?1-Agonist.- III. ?2-Antagonists (Phentolamine, Yohimbine).- IV. ?2-Agonist.- V. ?-Adrenergic Antagonists.- VI. ?-Adrenergic Agonists.- VII. In Conclusion.- D. Dopamine Agonists and Antagonists.- I. Dopamine2-Agonists.- II. Dopamine2-Antagonists.- III. Dopamine1-Antagonists.- IV. In Conclusion.- E. Differential Regulation of Waking and PS by Catecholamines.- F. Summary.- References.- 5 The Serotoninergic System and Sleep-Wakefulness Regulation.- A. The Serotoninergic System.- I. Serotoninergic Nuclei and Pathways.- II. Serotoninergic Metabolism and Neurotransmission.- 1. Synthesis of Serotonin.- 2. Release and Inactivation of Serotonin.- 3. Impairment of the Synthesis, Release and Catabolism of Serotonin.- III. Serotoninergic Receptors.- 1. 5-HT1A Receptors.- 2. 5-HT2 Receptors.- 3. 5-HT3 Receptors.- 4. 5-HT4 Receptors.- IV. Conclusion.- B. Serotonin and Sleep.- I. Spontaneous Activity of the Serotoninergic System During Sleep and Wakefulness.- II. Pharmacological Impairment of Serotoninergic Neurotransmission.- 1. Enhancement of Serotonin Levels in the Brain.- 2. Decrease in Serotonin Levels in the Brain.- III. Pharmacological Impairment of Receptor Function.- 1. 5-HT1A Receptors.- 2. 5-HT1B and 5-HTlC Receptors.- 3. 5-HT2 Receptors.- 4. 5-HT3 Receptors.- 5. Interaction Between the Various Serotoninergic Receptor Types.- IV. How Is Serotonin Involved in Sleep-Wakefulness Regulation?.- C. Summary.- References.- 6 Pharmacology of the Histaminergic System.- A. Introduction.- B. Histamine Synthesis and Metabolism.- C. Histaminergic Nuclei and Pathways.- D. Histamine Receptors.- E. Effects of Histamine at the Cellular Level.- F. Drugs Acting at the Histamine Receptors.- I. H1 Receptor.- II. H2 Receptor.- III. H3 Receptor.- G. Histamine Control of the Waking State.- I. Electrophysiological Studies.- II. Circadian Rhythms.- III. Lesion Studies.- IV. Pharmacological Studies.- 1. Intracerebroventricular Administration of Histamine.- 2. Histamine Synthesis Inhibition.- 3. H1 Receptor Agonists and Antagonists.- 4. H2 Receptor Agonists and Antagonists.- 5. H3 Receptor Agonists and Antagonists.- H. Summary.- References.- 7 Pharmacology of the Cholinergic System.- A. Introduction.- B. Biochemistry, Anatomy, and Physiology of the Cholinergic System.- I. Biochemistry.- 1. Synthesis.- 2. Storage and Release.- II. Anatomy.- 1. Cholinergic Cells.- 2. Basal Forebrain Cholinergic Groups.- 3. Brain Stem Cholinergic Groups.- III. Cholinergic Receptors.- 1. Nicotinic Receptors.- 2. Muscarinic Receptors.- IV. Postsynaptic Effects.- C. Cholinergic System and Sleep.- I. Spontaneous Activity of Cholinergic Neurons.- 1. Nucleus Basalis.- 2. LDT/PPT.- II. Spontaneous Release of Ach.- III. Availability of Cholinergic Receptors and AChE.- IV. Lesions of the Cholinergic System.- 1. Lesions and Stimulation of Basal Forebrain.- 2. Lesions of LDT/PPT.- V. Pharmacological Manipulations of the Cholinergic System.- 1. Cortical Activation.- 2. Hippocampal Theta Rhythm.- 3. REM Sleep.- 4. ACh and Atonia.- 5. ACh and PGO Waves.- 6. Diseases Involving ACh and Sleep.- D. Cholinergic System and Postural Mechanisms.- I. Effects on Decerebrate Rigidity.- II. Effects on Vestibulospinal Reflexes.- III. Effects on Postural Adjustments During Cortically Induced Movements.- IV. Cerebellar Regulation of Vestibular Reflexes.- E. Cholinergic System and Respiratory Mechanisms.- F. Conclusions.- I. Cholinergic System and Cortical Activation.- II. Cholinergic System and REM Sleep.- III. Cholinergic System and Postural Mechanisms.- G. Summary.- References.- 8 Pharmacology of the GABAergic/Benzodiazepine System.- A. Introduction.- B. Functional Evidence for the GABA-mimetic Properties of Benzodiazepines.- I. Electrophysiology.- II. Pharmacology and Biochemistry.- III. Histochemistry.- IV. Receptor Interactions: Effects of GABA Receptor-Agonists on Benzodiazepine-Receptor Binding and Vice Versa.- C. GABAA Receptor — Benzodiazepine Receptor — Chloride Channel Complex.- I. Functional Aspects.- II. Structural Aspects.- III. Chain of Events from Benzodiazepine-Receptor Occupation to Pharmacological Response.- IV. Benzodiazepine-Receptor Ligands with Different Intrinsic Activities: Concept of Agonists, Antagonists, and Inverse Agonists.- V. Receptor Subclassess and Hypnotic Benzodiazepines.- VI. Relationship Between Benzodiazepine-Receptor Affinity and Biological Activity.- D. Specific Hypnotic Drugs.- I. Benzodiazepines.- II. Barbiturates.- III. Zopiclone and Zolpidem.- E. Summary.- References.- 9 Pharmacology of the CNS Peptides.- A. Introduction.- B. Delta-Sleep-Inducing Peptide: A Circadian Programmer?.- I. Research Background.- II. Distribution and Biosynthesis in the Brain.- III. Circadian Sleep-Waking Rhythm.- IV. Sleep-Promoting Activity of Structural Analogs.- V. Aspects of “Extra-Sleep”Activities and Neurotransmitter Systems.- 1. Antinociceptive Activity and Sleep.- 2. Thermoregulation.- VI. Concluding Remarks.- C. Glutathione: A Neuronal Detoxification Factor?.- I. Research Background.- II. Sleep-Modulatory Activity of Oxidized Glutathione.- 1. Bioassay.- 2. Effects on Sleep.- 3. Effects on Brain Temperature.- III. Sleep-Modulatory Activity of Reduced Glutathione.- IV. Possible Mechanisms.- D. Muramyl Peptides and Cytokines: Somnopyrogenic Immunomodulators?.- I. Research Background.- II. Muramyl Peptides and Infectious Diseases.- 1. Bacterial and Viral Infections and Sleep.- 2. Cerebral Site of Action.- III. Interleukin-1.- 1. Somnopyrogenic Activities.- 2. Transport.- 3. IL-1 Receptors.- 4. Interactions with Other Sleep Substances.- IV. Tumor Necrosis Factor.- V. Interferon.- VI. Integrative Remarks.- E. Hypothalamo-hypophyseal Hormones: Neuroendocrine Transducers?.- I. Research Background.- II. Growth Hormone-Related Hormones.- III. Corticotropin-Related Hormones.- IV. Thyrotropin-Related Hormones.- V. Prolactin.- VI. Concluding Remarks.- F. Satiety-Related Substances: Ischymetric Factors or Postprandial Somnogens?.- I. Research Background.- II. Cholecystokinin.- III. Bombesin.- IV. Acidic Fibroblast Growth Factor.- V. Concluding Remarks.- G. Vasoactive Intestinal Polypeptide and Vasopressin: Circadian Timekeepers or REM Sleep Factors?.- H. Vasotocin: A Brain Maturation Modulator?.- I. General Concluding Remarks.- J. Summary.- References.- 10 Hormones and Sleep.- A. Introduction.- B. Interactions Between Sleep, Circadian Rhythmicity and Hormonal Release.- C. Methodology of Studies of Sleep and Hormonal Secretion.- I. Design of Experimental Protocols.- II. Analysis of Hormonal Data.- III. Analysis of the Interaction Between Sleep and Hormonal Release.- D. Modulation of Hormonal Release by Sleep and Wake.- I. Corticotropic Axis.- II. Somatotropic Axis.- III. Thyrotropic Axis.- IV. Lactotropic Axis.- V. Gonadotropic Axis.- VI. Glucose Tolerance and Insulin Secretion.- VII. Hormones Regulating Water Balance.- E. Sleep-Promoting Effects of Hormones.- I. Growth Hormone-Releasing Hormone and Growth Hormone.- II. Melatonin.- F. Conclusions.- G. Summary.- References.- 11 Pharmacology of the Adenosine System.- A. Introduction.- B. Effects of Adenosine and Adenosine-Related Compounds on Sleep.- I. Intracerebroventricular Administration of Adenosine and Sleep in Rats.- II. Microinjections of Adenosine to Preoptic Area and Sleep in Rats.- III. Inhibition of Adenosine Deaminase and Sleep.- IV. Adenosine Analogs and Sleep.- C. Adenosine A1 Receptors in Sleep and Waking.- I. Central A1 Receptor Variation During the Circadian Period.- II. Central A1 Receptors in Young and Old Rats.- III. Central A1 Receptors in REM Sleep Deprivation.- D. Methylxanthines and Sleep: Effects of Blockade of Adenosine A1 and/or Adenosine A2 Receptors.- I. Caffeine and Adenosine Agonists: Behavioral Interaction.- II. Dose-Response Effects of Caffeine on Sleep.- III. Caffeine Blocks Both Adenosine A1 and A2 Receptors: Is the Blockade of A1 Receptors More Important for CNS Stimulation?.- E. Benzodiazepines and Central Adenosine Receptors.- I. Diazepam and Adenosine Receptors in Specific Brain Areas in Rats.- II. Triazolam and Central Adenosine Receptors.- III. Inhibition of Adenosine Transport and Central Adenosine Receptors.- F. Hypothesis for Adenosine Hypnotic Action.- G. Conclusions.- H. Summary.- References.- 12 Methodological Issues in Pharmacological Studies of Sleep.- A. Introduction.- B. Objectives of the Phases of Investigation of a New Hypnotic.- C. Methods of Measurement.- I. Pharmacokinetic.- II. Efficacy.- 1. Objective Measures.- 2. Subjective Estimates.- III. Safety.- 1. Objective Measures.- 2. Patient Reports.- D. Design and Analysis Considerations.- I. Phase I Studies.- II. Phase II Studies.- 1. Design of Phase II Studies.- 2. General Issues: Sleep Laboratory Studies.- 3. General Issues: Clinical Trials.- 4. General Issues: Studies of Effects on Daytime Performance.- III. Phase III Studies.- IV. Phase IV Studies.- E. Summary.- References.- 13 Hypnotic Drugs.- A. Introduction.- B. The Condition of Insomnia.- I. Treatment of Insomnia.- C. Development of Benzodiazepines and Other Hypnotic Drugs.- I. Evaluation of Hypnotic Drugs.- D. 1,4-Benzodiazepines with Slow Elimination and Low Binding Affinity.- I. Flurazepam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- II. Quazepam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- E. 1,4-Benzodiazepines with Intermediate to Slow Elimination and Moderate Binding Affinity.- I. Nitrazepam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- F. 1,4-Benzodiazepines with Rapid to Intermediate Elimination and Low Binding Affinity.- I. Temazepam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- G. 1,4-Benzodiazepines with Rapid to Intermediate Elimination and Moderate to High Binding Affinity.- I. Flunitrazepam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- II. Loprazolam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- III. Lormetazepam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- H. 1,4-Benzodiazepines with Rapid Elimination and High Binding Affinity.- I. Midazolam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- I. Triazolobenzodiazepines.- I. Brotizolam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- II. Estazolam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- III. Triazolam.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- J. New Non-Benzodiazepine Hypnotics.- I. Zopiclone.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- II. Zolpidem.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- K. Conclusions on Efficacy of Hypnotic Drugs.- L. Conclusions on Underlying Mechanisms for Adverse Events.- I. Pharmacokinetic Factors.- II. Pharmacodynamic Factors.- III. Special Properties Related to Chemical Structure.- M. Comments on Drug-Induced Sleep Stage Alterations.- N. Summary.- References.- 14 Anxiolytic Drugs.- A. Introduction.- B. Anxiolytic Drugs and Sleep: Overview.- C. Benzodiazepines.- I. 1,4-Benzodiazepines with Slow Elimination and Low Binding Affinity.- 1. Ketazolam.- 2. Chlordiazepoxide.- 3. Clorazepate.- 4. Fosazepam.- II. 1,4-Benzodiazepines with Intermediate to Slow Elimination and Moderate to High Binding Affinity.- 1. Clonazepam.- 2. Diazepam.- III. 1,4-Benzodiazepines with Rapid to Intermediate Elimination and Low Binding Affinity.- 1. Oxazepam.- IV. 1,4-Benzodiazepines with Rapid to Intermediate Elimination and Moderate to High Binding Affinity.- 1. Lorazepam.- V. Triazolobenzodiazepines.- 1. Alprazolam.- 2. Adinazolam.- D. Non-Benzodiazepines, GABAA Agonists.- I. Cyclopyrrolons.- 1. Suriclone.- II. Imidazopyridines.- 1. Alpidem.- E. ?-Adrenoceptor Antagonists.- I. ?-Blockers with High Lipophilicity.- 1. Propranolol.- II. ?-Blockers with Moderate Lipophilicity.- 1. Metoprolol.- 2. Pindolol.- III. ?-Blockers with Low Lipophilicity.- 1. Acebutolol.- 2. Atenolol.- 3. Nadolol.- 4. Sotalol.- F. ?2-Receptor-Agonists.- I. Clonidine.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- II. Guanfacine.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- G. Serotonin Receptor-Agonists.- I. Buspirone.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- H. Serotonin Receptor-Antagonists.- I. Ritanserin.- 1. Efficacy.- 2. Withdrawal Effects.- 3. Side Effects.- I. Summary.- References.- 15 Stimulant Drugs.- A. Early Use of Plant Preparations Containing Central Stimulants.- B. Indications for Medical Use of Central Stimulant Drugs.- C. Clinical Features of Narcolepsy and Other Hypersomniac Conditions.- I. Narcolepsy.- II. Idiopathic Hypersomnia.- III. Recurrent Hypersomnia.- D. Central Stimulants.- I. Caffeine.- II. Ephedrine.- III. Amphetamine and Methamphetamine.- IV. Methylphenidate.- V. Pemoline.- VI. Mazindol.- VII. Modafinil.- E. Treatment of Narcolepsy and Other Hypersomniac Conditions with Central Stimulants and Other Adjunctive Drugs.- I. Narcolepsy.- II. Idiopathic Hypersomnia.- III. Recurrent Hypersomnia.- F. Other Problems Related to the Use of Central Stimulant Drugs.- G. Summary.- References.- 16 Neuroleptics, Antihistamines and Antiparkinsonian Drugs: Effects on Sleep.- A. Introduction.- B. Neuroleptics.- I. Introduction.- II. Phenothiazines.- 1. Chlorpromazine.- 2. Other Phenothiazines.- III. Butyrophenones.- IV. Nonclassical Neuroleptics.- 1. Sulpiride.- 2. Clozapine.- 3. Remoxipride.- 4. Ritanserin.- V. Clinical Implications.- C. Antihistamines.- I. Introduction.- II. Sedative Antihistamines.- III. Nonsedative Antihistamines.- IV. Clinical Implications.- D. Antiparkinsonian Drugs.- I. Introduction.- II. Dopaminergic Antiparkinsonian Drugs.- III. Anticholinergic Antiparkinsonian Drugs.- IV. Clinical Implications.- E. Summary.- References.- 17 Antidepressant and Antimanic Drugs.- A. Introduction.- B. The Antidepressant Drugs.- I. Mechanisms of Action.- II. Classification.- 1. Sedative and Nonsedative Antidepressants.- 2. Effects on Norepinephrine, Dopamine and Serotonin.- III. An Integrative Model for Depression.- IV. Sleep and Depression.- V. Effects of Antidepressants on Sleep.- 1. Effects of Antidepressants on REM Sleep.- 2. Effects of Antidepressants on Other Sleep Stages.- VI. Use of Antidepressants in Sleep-Related Disorders.- 1. Psychophysiological Insomnia.- 2. Sleep Apnea Syndrome.- 3. Narcolepsy.- C. Antimanic Drugs.- I. Lithium.- II. Carbamazepine.- D. Summary.- References.- 18 Anticonvulsant Drugs.- A. Introduction.- B. Drug Reviews.- I. Phenobarbital.- II. Phenytoin.- III. Carbamazepine.- IV. Valproate.- V. Ethosuximide.- C. Summary.- References.- 19 Mechanisms of Benzodiazepine Drug Dependence.- A. Introduction.- B. Prevalence of Benzodiazepine Dependence.- C. Description of Benzodiazepine-Withdrawal Symptoms.- I. Most Frequent Withdrawal Symptoms Associated with Benzodiazepine Use and Discontinuation.- 1. Daytime Anxiety, Early Morning Insomnia and Other Hyperexcitability Phenomena During Drug Administration.- 2. Rebound Insomnia and Anxiety Following Drug Withdrawal.- II. Less Frequent but Severe Withdrawal Phenomena Following Benzodiazepine Discontinuation.- D. Risk Factors Associated with Benzodiazepine Dependence.- I. Dose.- II. Duration of Drug Administration.- III. Gradual Versus Abrupt Discontinuation.- IV. Benzodiazepine Dependence and Patient Type.- 1. Subjects with Substance Abuse Disorders.- 2. Subjects with Psychiatric Disorders.- 3. Subjects with Sleep Disorders.- E. Pharmacological Properties Associated with Benzodiazepine Dependence.- I. Absorption Rate.- II. Elimination Rate.- III. Receptor-Binding Affinity.- IV. Benzodiazepine Effects on the LC-NE and HP A Axes.- 1. Tolerance, Daytime Anxiety and Other Hyperexcitability Phenomena During Drug Administration.- 2. Withdrawal Difficulties (Rebound Insomnia and Anxiety and Seizures).- V. Role of Other Neurotransmitters in Benzodiazepine Dependence.- VI. Conclusions.- F. Summary.- References.- 20 Sleep Disturbances as Side Effects of Therapeutic Drugs.- A. Factors Contributing to a Drug’s Capacity to Induce Sleep Disturbances.- B. Insomnia.- I. Stimulants.- II. Stimulant Antidepressants.- III. Hypnotics and Anxiolytics.- 1. Drug Withdrawal Insomnia.- 2. Early Morning Insomnia and Daytime Anxiety.- 3. Rebound Insomnia and Rebound Anxiety.- 4. Sleep Disturbances with Newer Anxiolytics.- IV. Corticosteroids.- V. Bronchodilators.- VI. Antihypertensives.- VII. Other Drugs.- C. Excessive Daytime Sleepiness.- I. Hypnotics and Anxiolytics.- II. Sedative Neuroleptics.- III. Sedative Antidepressants.- IV. Anticonvulsants.- V. Antihistamines.- D. Sleep Apnea.- I. CNS Depressants.- 1. Hypnotics.- 2. Narcotics.- 3. Anesthetics.- II. Antihypertensives.- III. Testosterone.- IV. Other Drugs.- E. Nocturnal Myoclonus.- F. Auxiliary Symptoms of Narcolepsy.- G. Somnambulism/Night Terrors.- I. Lithium.- II. Hypnotics.- III. Other Drugs.- H. REM Behavior Disorder.- I. Nightmares.- I. Antihypertensives.- II. Psychotropic Drugs.- III. Other Drugs.- J. Circadian Rhythm Disorders.- K. Summary.- References.